Medicines

14 pages, 2428 KB

Open AccessArticle

Preliminary Evaluation of an Injectable Therapeutic for Cisplatin Ototoxicity Using Neuronal SH-SY5Y Cells

by Michelle Hong, Katherine Kedeshian, Larry Hoffman and Ashley Kita

Medicines 2025, 12(4), 30; https://doi.org/10.3390/medicines12040030 - 9 Dec 2025

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Background/Objectives: Though ototoxic, cisplatin is a mainstay of chemotherapy for a variety of cancers. One suggested mechanism of cisplatin ototoxicity involves damage to the spiral ganglion afferent neurons in the inner ear. There is a need for a high-throughput model to screen medications [...] Read more.

Background/Objectives: Though ototoxic, cisplatin is a mainstay of chemotherapy for a variety of cancers. One suggested mechanism of cisplatin ototoxicity involves damage to the spiral ganglion afferent neurons in the inner ear. There is a need for a high-throughput model to screen medications for efficacy against cisplatin and to develop a local therapeutic to mitigate cisplatin’s debilitating side effects. Microparticles encapsulating a therapeutic medication are an injectable and tunable method of sustained drug delivery, and thus a promising treatment. Methods: SH-SY5y human neuroblastoma cells were used as a cell line model for the spiral ganglion neurons. The cells were dosed with cisplatin and four potential therapeutics (melatonin, metformin, cyclosporine, and N-acetylcysteine), with cell viability measured by CCK-8 assay. The most promising therapeutic, N-acetylcysteine (NAC), was then encapsulated into multiple poly(lactic-co-glycolic acid) (PLGA) microparticle subtypes of varied lactide–glycolide (L:G) ratios and NAC amounts. The elution profile of each microparticle subtype was determined over two months. Results: Of the therapeutics screened, only cells dosed with 1 or 10 mM NAC prior to cisplatin injury demonstrated an improvement in cell viability (73.8%, p < 1 × 10⁻⁸) when compared to cells dosed with cisplatin alone. The 75:25 L:G microparticles demonstrated an increase in the amount of NAC released compared to the 50:50 L:G microparticles. Conclusions: NAC is a potential therapeutic agent for cisplatin toxicity when tested in a neuronal cell line model. NAC was encapsulated into PLGA microparticles and eluted detectable concentrations of NAC for 6 days, which is a first step towards otoprotection for the weeks long duration of chemotherapy treatment. This work describes a method of screening potential therapeutics and a strategy to develop local drug eluting treatments to protect against cisplatin ototoxicity. Full article

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12 pages, 1617 KB

Open AccessArticle

Identification of Active Components in Connarus ruber Extract Exhibiting Anti-Glycation Effects

by Ryoji Taniguchi, Ryusuke Nakatsuka, Yuka Sasaki, Mariko Takenokuchi, Takashi Maoka, Tomio Iseki, Hirohito Kubo and Tadashige Nozaki

Medicines 2025, 12(4), 29; https://doi.org/10.3390/medicines12040029 - 3 Dec 2025

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Abstract

Background: Glycation, a non-enzymatic reaction between sugars and biomolecules, leads to the formation of advanced glycation end-products (AGEs), which are implicated in the progression of chronic diseases. Connarus ruber (Poepp.) Planch (C. ruber), a traditional medicinal plant used for diabetes, has [...] Read more.

Background: Glycation, a non-enzymatic reaction between sugars and biomolecules, leads to the formation of advanced glycation end-products (AGEs), which are implicated in the progression of chronic diseases. Connarus ruber (Poepp.) Planch (C. ruber), a traditional medicinal plant used for diabetes, has shown anti-glycation activity. This study aimed to identify the active components in C. ruber extract and elucidate their anti-glycation mechanisms. Methods: Using NMR and LC-MS analyses, we identified epicatechin and procyanidin A2 as major polyphenolic constituents. Collagen glycation assays were performed to evaluate the inhibitory effects of these compounds on fructose- and glyceraldehyde (GA)-induced glycation. Additionally, their cytoprotective effects were assessed using GA-induced cytotoxicity assays in dental pulp stem cells (DPSCs). Results: Both epicatechin and procyanidin A2 inhibited fructose- and GA-induced glycation in a dose-dependent manner, showing greater efficacy than aminoguanidine. Furthermore, these compounds significantly alleviated GA-induced cytotoxicity in DPSCs. Conclusions: These findings suggest that epicatechin and procyanidin A2 are candidate contributors to the anti-glycation and cytoprotective effects of C. ruber. The results support the potential of C. ruber extract as a source of therapeutic agents for glycation-related diseases and for enhancing stem cell viability. Full article

(This article belongs to the Section Oral Medicine and Dentistry)

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31 pages, 1106 KB

Open AccessReview

AΙ-Driven Drug Repurposing: Applications and Challenges

by Paraskevi Keramida, Nikolaos K. Syrigos, Marousa Kouvela, Garyfallia Poulakou, Andriani Charpidou and Oraianthi Fiste

Medicines 2025, 12(4), 28; https://doi.org/10.3390/medicines12040028 - 13 Nov 2025

Cited by 6 | Viewed by 5069

Abstract

Drug repurposing is the process of discovering new therapeutic indications for already existing drugs. By using already approved molecules with known safety profiles, this approach reduces the time, costs, and failure rates associated with traditional drug development, accelerating the availability of new treatments [...] Read more.

Drug repurposing is the process of discovering new therapeutic indications for already existing drugs. By using already approved molecules with known safety profiles, this approach reduces the time, costs, and failure rates associated with traditional drug development, accelerating the availability of new treatments to patients. Artificial Intelligence (AI) plays a crucial role in drug repurposing by exploiting various computational techniques to analyze and process big datasets of biological and medical information, predict similarities between biomolecules, and identify disease mechanisms. The purpose of this review is to explore the role of AI tools in drug repurposing and underline their applications across various medical domains, mainly in oncology, neurodegenerative disorders, and rare diseases. However, several challenges remain to be addressed. These include the need for a deeper understanding of molecular mechanisms, ethical concerns, regulatory requirements, and issues related to data quality and interpretability. Overall, AI-driven drug repurposing is an innovative and promising field that can transform medical research and drug development, covering unmet medical needs efficiently and cost-effectively. Full article

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13 pages, 252 KB

Open AccessArticle

Cannabis Use and Analgesic Prescribing in UK Primary Care: A Retrospective Cohort Study of Patients with Osteoarthritis

by Simon Erridge, Joht Singh Chandan, Krishna M. Gokhale, Christian Billinghurst and Mikael H. Sodergren

Medicines 2025, 12(4), 27; https://doi.org/10.3390/medicines12040027 - 10 Nov 2025

Cited by 1 | Viewed by 1838

Abstract

Objectives: This study aims to assess differences in analgesia prescribing in UK primary care between individuals with osteoarthritis who have a recorded exposure to cannabis use and those who do not. Methods: This population-based retrospective cohort study included opioid-naïve patients with osteoarthritis (aged [...] Read more.

Objectives: This study aims to assess differences in analgesia prescribing in UK primary care between individuals with osteoarthritis who have a recorded exposure to cannabis use and those who do not. Methods: This population-based retrospective cohort study included opioid-naïve patients with osteoarthritis (aged 25–85 years) who were active in Clinical Practice Research Datalink Aurum between 1 January 1995 and 15 December 2023. Patients with osteoarthritis who had current or historic cannabis use recorded were matched to two unexposed individuals by age, sex, smoking status, and health authority. Patients were followed up to assess prescriptions of analgesia. Cox regression was performed adjusted for age, sex, and ethnicity. Results: 662 exposed patients were matched to 1319 unexposed patients. Cannabis-exposed individuals were more likely to be prescribed opioids (adjusted hazard ratio (HR): 2.06; 95% confidence interval (CI): 1.74–2.43; p < 0.001), gabapentinoids (HR: 3.31; 95% CI: 2.34–4.67; p < 0.001), non-steroidal anti-inflammatory drugs (HR: 1.99; 95% CI: 1.72–2.31; p < 0.001), tricyclic antidepressants (HR: 2.64; 95% CI: 2.03–3.44; p < 0.001), other antidepressants (HR: 7.22; 95% CI: 5.24–9.94; p < 0.001), and paracetamol (HR: 3.30; 95% CI: 2.43–4.48; p < 0.001). Conclusions: This study suggests there is an association between coded exposure to cannabis in UK primary care records and increased prescribing of analgesia. Given the relative scarcity of recorded cannabis use relative to its prevalence in the general population, these findings must be interpreted cautiously. The increased hazard of using analgesia and mortality within the cannabis-exposed cohort may be confounded by socioeconomic status and a higher likelihood of coding cannabis use in those experiencing adverse effects after consumption or cannabis misuse disorder. Full article

21 pages, 4067 KB

Open AccessArticle

HDAC5 Inhibition as a Therapeutic Strategy for Titin Deficiency-Induced Cardiac Remodeling: Insights from Human iPSC Models

by Arif Ul Hasan, Sachiko Sato, Mami Obara, Yukiko Kondo and Eiichi Taira

Medicines 2025, 12(4), 26; https://doi.org/10.3390/medicines12040026 - 27 Oct 2025

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Abstract

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN [...] Read more.

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies. Full article

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12 pages, 892 KB

Open AccessArticle

Checklist-Based Identification of Adverse Drug Reactions in Emergency Department Patients

by Benjamin J. Hellinger, Thilo Bertsche, Yvonne Remane and André Gries

Medicines 2025, 12(4), 25; https://doi.org/10.3390/medicines12040025 - 17 Oct 2025

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Abstract

Background: Patients presenting at the emergency department (ED) have a wide variety of complaints. In some of those patients a possible reason for their complaints might be an adverse drug reaction (ADR). An appropriate identification of ADR in this setting is required to [...] Read more.

Background: Patients presenting at the emergency department (ED) have a wide variety of complaints. In some of those patients a possible reason for their complaints might be an adverse drug reaction (ADR). An appropriate identification of ADR in this setting is required to optimize drug therapy and to prevent serious harm deriving from an overlooked ADR. Methods: This retrospective study assessed medical records of patients for ADR as a reason for the ED presentation in two assessments. In the first assessment, medical records were evaluated for potential ADR leading to ED presentation with a predefined checklist by an examiner not involved in initial patient treatment. In the second assessment the same medical records were assessed for ADR identified by the physician in the initial patient presentation. Discrepancies in identified ADR were compared. For descriptive data analysis and statistical evaluation, the McNemar test was performed. Results: From 35,333 patients admitted to the ED, full data were available from 34,747 patients for evaluation. In those patients, 2071 (6.0%) ADR were identified as being the reason for ED presentation by using the checklist. In 828 (2.4%) patients, emergency department physicians had documented an ADR in the medical records. By using the checklist, ADR identification could be improved significantly as compared to routine care, at 6.0% vs. 2.4%, respectively (p < 0.001). The most common chief complaint in patients with an ADR was worsened general condition. Most common drug class causing ADR were antithrombotics. Conclusions: ADR seem to be overlooked in routine care since a significantly higher number of ADR were found by using a checklist-based method as compared to ADR documented as part of routine examination. Therefore, implementing the checklist in the routine process might improve ADR identification. Full article

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13 pages, 1524 KB

Open AccessArticle

Impact of Sampling Strategy and Population Model on Bayesian Estimates of Vancomycin AUC in Patients with BMI > 40 kg/m²: A Single-Center Retrospective Study

by Sarah A. Ekkelboom, Soraya M. Hobart, Laurie J. Barten and Staci L. Hemmer

Medicines 2025, 12(4), 24; https://doi.org/10.3390/medicines12040024 - 30 Sep 2025

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Abstract

Background/Objectives: Growing evidence supports the use of a single trough concentration, rather than both a peak and trough, to estimate the 24 h area under the curve (AUC₂₄) of vancomycin using Bayesian software (InsightRx^® Ver.1.71). However, patients with body [...] Read more.

Background/Objectives: Growing evidence supports the use of a single trough concentration, rather than both a peak and trough, to estimate the 24 h area under the curve (AUC₂₄) of vancomycin using Bayesian software (InsightRx^® Ver.1.71). However, patients with body mass index (BMI) ≥ 40 kg/m² are underrepresented in validation studies. Studies in patients with obesity have produced mixed results, potentially because of different population models used. Methods: This single-center, retrospective study evaluated adult inpatients with BMI ≥ 40 kg/m². Steady-state AUC₂₄ estimates generated by Bayesian software using both two-concentration and one-concentration inputs were compared. Agreement was defined as a percent difference within ±20%. Subgroup analyses were conducted for patients with defined peak and trough concentrations and for comparisons between two Bayesian population models (Carreno vs. Hughes). Linear regression assessed covariates associated with percent difference. Results: Among 82 encounters, 97.5% of one-concentration estimates based on the smaller concentration were within ±20% of the two-concentration AUC_24,SS (mean difference: 2.9%, 95% CI: 0.14 to 3.8%). Similar agreement was observed using the larger concentration (97.5%, mean difference: −3.1%, 95% CI: −4.7 to −0.1.5%). Subgroup analysis for encounters with true peak/trough levels (n = 22) also showed 100% agreement within ±20%. The percent difference did not correlate with BMI or other covariates. Comparison of Hughes vs. Carreno models showed larger variability (only 59.1% within ±20%). Conclusions: In patients with BMI ≥ 40 kg/m², Bayesian AUC_24,SS estimation using a single vancomycin concentration is feasible. Greater caution is warranted in the setting of acute kidney injury, poor model fit, or targeting AUC at the extremes of the therapeutic range. The population model used to generate the Bayesian AUC estimate has a much greater influence than the number of concentrations analyzed. Furthermore, measuring two concentrations does not ensure concordance between models. Full article

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17 pages, 1617 KB

Open AccessSystematic Review

Levosimendan in Decompensated Heart Failure with Reduced Ejection Fraction in Older Adults: A Systematic Review of Safety and Efficacy

by Esteban Zavaleta-Monestel, Jeaustin Mora-Jiménez, Kevin Cruz-Mora, Ernesto Martinez-Vargas, José Pablo Díaz-Madriz, Sebastián Arguedas-Chacón, Abigail Fallas-Mora, Carlos Wu-Chin and Jose Miguel Chaverrí-Fernandez

Medicines 2025, 12(4), 23; https://doi.org/10.3390/medicines12040023 - 30 Sep 2025

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Abstract

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and functional decline in older adults, accounting for over 80% of all heart failure cases. Given the narrow therapeutic window of currently available inotropes and the vulnerability of this [...] Read more.

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and functional decline in older adults, accounting for over 80% of all heart failure cases. Given the narrow therapeutic window of currently available inotropes and the vulnerability of this population, levosimendan has been proposed as a potential alternative. This systematic review aimed to evaluate the clinical efficacy and safety of levosimendan in older adults with decompensated HFrEF. Methods: A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted between January and May 2025, following PRISMA 2020 guidelines. The review was registered in PROSPERO (CRD420251032329). Of 379 articles initially identified, 8 studies (randomized, observational, and single-arm designs) enrolling patients aged ≥65 years with decompensated HFrEF met the inclusion criteria. Study quality was assessed using the Cochrane RoB-2 tool and JBI Critical Appraisal Checklists. No meta-analysis was performed due to heterogeneity in study designs, populations, and interventions. Results: A total of 2838 patients were analyzed. Levosimendan was associated with short-term improvements in hemodynamic parameters, including an increase in cardiac index (from 1.65 to 2.37 L/min/m²) and a reduction in pulmonary capillary wedge pressure (from 31 to 16 mmHg) within 24–72 h (p < 0.002). However, no statistically significant differences were observed in 30-, 90-, or 180-day mortality (p > 0.05), and findings on rehospitalization were inconsistent. Reported adverse events included hypotension (36–57%) and atrial arrhythmias (9–50%), with low treatment discontinuation rates (5–8%). Conclusions: Levosimendan may improve short-term hemodynamic parameters in older adults with decompensated HFrEF, but the available evidence is limited and heterogeneous. Its effects on mortality and rehospitalization remain inconclusive. Clinical use should be individualized and closely monitored, particularly in frail patients. Full article

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